肿瘤细胞治疗研究
英文原题：Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study.
Efficacy and safety of novel multiple-chain DAP-CAR-T cells targeting mesothelin in ovarian cancer and mesothelioma: a single-arm, open-label and first-in-human study.
我们的研究突出了靶向 MSLN 的多链 DAP-CAR-T 细胞疗法治疗卵巢癌和间皮瘤患者的安全性和疗效。
背景：嵌合抗原受体（CAR）T细胞治疗血液系统恶性肿瘤已取得显著成效，但治疗实体瘤的效果仍较差，并面临多项临床应用挑战。我们此前发现，多链DNAX活化蛋白（DAP）CAR结构可提高CAR-T细胞治疗实体瘤的安全性和疗效。尤其是靶向间皮素（MSLN）的CAR-T细胞疗法，在卵巢癌和间皮瘤等MSLN阳性实体瘤中具有治疗潜力。 方法：采用体外细胞杀伤实验和异种移植模型，评估MSLN靶向DAP-CAR-T细胞及其他CAR-T细胞的抗肿瘤效力。通过ELISA和流式细胞术分析细胞因子分泌能力和增殖能力。另招募8例MSLN表达患者，评估MSLN-DAP CAR-T细胞疗法的安全性和疗效。采用单细胞测序探究患者治疗期间免疫细胞动态，并鉴定与疗效和毒性相关的转录组特征。 结果：我们发现，将天然杀伤细胞免疫球蛋白样受体截短体与DAP12组合形成的多链DAP-CAR，较其他与DAP12、DAP10或CD3ζ关联的NK细胞活化受体具有更好的细胞毒性和肿瘤杀伤能力。在一项单臂、开放标签临床试验（ChiCTR2100046544）中评估MSLN-DAP CAR-T细胞疗法治疗卵巢癌和间皮瘤患者的安全性和疗效；2例患者达到部分缓解，另4例病情稳定。此外，单细胞测序分析提示，输注KT032 CAR-T细胞可招募更多免疫细胞，并暂时重塑肿瘤微环境。 结论：本研究凸显了靶向MSLN的多链DAP-CAR-T细胞疗法在治疗卵巢癌和间皮瘤患者中的安全性和治疗效力。 试验注册：ChiCTR.org.cn，ChiCTR2100046544。
BACKGROUND: Despite remarkable achievements in applying chimeric antigen receptor (CAR)-T cells to treat hematological malignancies, they remain much less effective against solid tumors, facing several challenges affecting their clinical use. We previously showed that multichain DNAX-activating protein (DAP) CAR structures could enhance the safety and efficacy of CAR-T cells when used against solid tumors. In particular, mesothelin (MSLN)-targeted CAR-T cell therapy has therapeutic potential in MSLN-positive solid tumors, including ovarian cancer and mesothelioma. METHODS: In vitro cell killing assays and xenograft model were utilized to determine the anti-tumor efficacy of MSLN targeting DAP-CAR-T cells and other CAR-T cells. ELISA and flow cytometry analysis were used to assess the cytokine secretion capacity and proliferation ability. Eight patients with MSLN expression were enrolled to evaluate the safety and efficacy of MSLN-DAP CAR-T cell therapy. Single-cell sequencing was performed to explore the dynamics of immune cells in patients during treatment and to identify the transcriptomic signatures associated with efficacy and toxicity. RESULTS: We found that multichain DAP-CAR formed by combining a natural killer cell immunoglobulin-like receptor truncator and DAP12 exhibited better cytotoxicity and tumor-killing capacity than other natural killer cell-activated receptors associated with DAP12, DAP10, or CD3Z. The safety and efficacy of MSLN-DAP CAR-T cell therapy in patients with ovarian cancer and mesothelioma were evaluated in a single-arm, open-label clinical trial (ChiCTR2100046544); two patients achieved partial response, while four patients had a stable disease status. Furthermore, single-cell sequencing analysis indicated that KT032 CAR-T cell infusion could recruit more immune cells and temporarily remodel the TME. CONCLUSIONS: Our study highlights the safety and therapeutic efficacy of multiple-chain DAP-CAR-T cell therapy targeting MSLN to treat patients with ovarian cancer and mesothelioma. TRIAL REGISTRATION: ChiCTR.org.cn, ChiCTR2100046544 . May 21, 2021.
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